In a groundbreaking advancement for metabolic biology, recent research reveals that the liver’s capacity for glucose production is far more dynamic and spatially intricate than previously understood. Scientists have uncovered a remarkable plasticity in hepatocyte function, demonstrating that these liver cells adapt their gluconeogenic activity according to their precise location within the liver lobule and the body’s nutritional state. This spatial and temporal heterogeneity of glucose metabolism challenges traditional paradigms and offers new insights into the metabolic transitions experienced during feeding, fasting, and starvation.
The liver lobule, characterized by its hexagonal arrangement, forms the fundamental structural and functional unit of the liver. Hepatocytes, the principal parenchymal cells of the liver, are organized along the axis stretching from the portal triad—where oxygen-rich blood enters—to the central vein, where deoxygenated blood exits. Within this microanatomical framework, hepatocytes display distinct metabolic programs shaped by their microenvironment, including oxygen availability, nutrient gradients, and signaling molecules. These location-dependent metabolic profiles emphasize the liver’s capability for spatial specialization and adaptability.
Central among the liver’s metabolic functions is gluconeogenesis, the synthesis of glucose from non-carbohydrate precursors, which becomes paramount during periods of diminished dietary glucose intake such as fasting and starvation. Until now, the prevailing view held that gluconeogenesis was predominantly the domain of periportal hepatocytes—those located adjacent to the portal triad—owing to their access to substrates and signaling cues favoring glucose production. However, emerging evidence from single-cell transcriptomic analyses challenges this simplification by illuminating a more graded and dynamic landscape of gluconeogenic gene expression across the lobule.
In the fed state, hepatocyte gluconeogenic gene expression is relatively quiescent, reflecting the satiation of systemic glucose demands by dietary sources. Interestingly, periportal hepatocytes exhibit the earliest and most pronounced increase in gluconeogenic gene expression during the initial stages of fasting. This periportal activation is consistent with their strategic positioning receiving nutrient-rich blood and their known enzymatic complement tailored for glucose synthesis. Such metabolic tuning aids in maintaining stable blood glucose levels when dietary inputs wane.
As fasting endures, a fascinating shift occurs within the metabolic orchestra of the liver lobule. The traditionally gluconeogenically quiescent pericentral hepatocytes—those neighboring the central vein—begin to amplify their gluconeogenic gene expression and enzymatic activity. This wave of pericentral activation suggests an orchestrated expansion of glucose-producing capacity deeper within the lobule. Eventually, at the threshold of starvation, pericentral hepatocytes display gluconeogenic activity comparable to their periportal counterparts, underscoring a lobule-wide mobilization of glucose synthesis in response to energetic stress.
This spatial plasticity is not a mere byproduct of substrate availability but involves intricate regulatory networks. Starvation induces significant suppression of canonical β-catenin signaling within hepatocytes, a pathway previously implicated in liver zonation and metabolic regulation. Downregulation of β-catenin reprograms gene expression profiles, particularly influencing the expression of enzymes critical for glutamine metabolism—glutamine synthetase localized pericentrally and glutaminase near the periportal zone. This modulation enhances the integration of glutamine, an amino acid substrate, into gluconeogenic pathways, thereby expanding the molecular toolkit for glucose production under nutrient scarcity.
The incorporation of glutamine into glucose synthesis pathways during starvation reveals an additional layer of metabolic flexibility, challenging earlier conceptions that predominantly highlighted lactate and glycerol as gluconeogenic precursors. By adjusting both the spatial distribution of enzymatic activity and the types of substrates utilized, hepatocytes fine-tune systemic glucose homeostasis, ensuring survival during prolonged energy deficits.
Beyond its fundamental biological implications, this discovery reshapes our understanding of hepatic insulin resistance and systemic glucose production, phenomena intimately tied to metabolic diseases such as diabetes and non-alcoholic fatty liver disease. Traditional assessments that treat the liver as a homogenous organ may overlook the nuanced, localized responses of hepatocytes, obscuring accurate characterization of disease states and therapeutic responses.
Moreover, the recognition of spatial and temporal hepatocyte plasticity invites a reconsideration of pharmacological strategies targeting hepatic glucose production. Therapeutic interventions modulating gluconeogenesis might need to account for lobule-specific effects and dynamic metabolic states, potentially inspiring novel approaches that precisely target hepatocyte subpopulations to restore metabolic balance.
This research also underscores the power of single-cell analytical technologies in unraveling complex organ functions. By resolving gene expression patterns at unprecedented resolution within the liver lobule, scientists have exposed the hidden heterogeneity of cellular metabolic programs that were once masked in bulk analyses.
Future studies will likely investigate how other lobule-intrinsic factors—such as oxygen gradients, innervation, and local cytokine milieus—influence hepatocyte plasticity. Additionally, the interplay between hepatocyte zonation and systemic hormonal signals during diverse nutritional states remains a fertile ground for exploration.
Understanding hepatocyte metabolic diversity could also shed light on liver regeneration and repair, processes requiring dynamic shifts in cellular function and phenotype. Insights into these mechanisms may facilitate improved treatments for liver injury and enhance outcomes for patients undergoing liver transplantation.
In sum, the liver emerges not as a static metabolic factory but as a highly structured yet flexible tissue, capable of reconfiguring its cellular functions spatially and temporally to meet systemic energetic demands. This nuanced perspective bridges molecular signaling, cellular metabolism, and organ physiology, propelling the field toward a more comprehensive model of hepatic function in health and disease.
The implications of this study resonate across disciplines, offering new vistas for understanding energy homeostasis, metabolic disease pathogenesis, and the physiological adaptations underpinning survival in fluctuating nutritional environments. As science continues to decipher the complexity of liver function, the advent of spatially and temporally resolved metabolic profiling promises to revolutionize diagnostics and therapeutics in metabolic medicine.
Subject of Research: Hepatocyte spatial and temporal plasticity in gluconeogenesis during metabolic transitions.
Article Title: Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.
Article References:
Okada, J., Landgraf, A., Xiaoli, A.M. et al. Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01269-y
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